2,4-dioxo-3-quinazolinylaryl sulfonylureas

ABSTRACT

2,4-Dioxo-3-quinazolinylaryl sulfonylurea compounds are provided that are useful for the inhibition of ADP-platelet aggregation, particularly in the treatment of thrombosis and thrombosis related conditions or disorders.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application Ser. No.60/508,564, filed Oct. 3, 2003, the disclosure of which is incorporatedherein by reference.

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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

Thrombotic complications are a major cause of death in theindustrialized world. Examples of these complications include acutemyocardial infarction, unstable angina, chronic stable angina, transientischemic attacks, strokes, peripheral vascular disease,preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminatedintravascular coagulation and thrombotic cytopenic purpura. Thromboticand restenotic complications also occur following invasive procedures,e.g., angioplasty, carotid endarterectomy, post CABG (coronary arterybypass graft) surgery, vascular graft surgery, stent placements andinsertion of endovascular devices and protheses. It is generally thoughtthat platelet aggregates play a critical role in these events. Bloodplatelets, which normally circulate freely in the vasculature, becomeactivated and aggregate to form a thrombus with disturbed blood flowcaused by ruptured atherosclerotic lesions or by invasive treatmentssuch as angioplasty, resulting in vascular occlusion. Plateletactivation can be initiated by a variety of agents, e.g., exposedsubendothelial matrix molecules such as collagen, or by thrombin whichis formed in the coagulation cascade.

An important mediator of platelet activation and aggregation is ADP(adenosine 5′-diphosphate) which is released from blood platelets in thevasculature upon activation by various agents, such as collagen andthrombin, and from damaged blood cells, endothelium or tissues.Activation by ADP results in the recruitment of more platelets andstabilization of existing platelet aggregates. Platelet ADP receptorsmediating aggregation are activated by ADP and some of its derivativesand antagonized by ATP (adenosine 5′-triphosphate) and some of itsderivatives (Mills, D. C. B. (1996) Thromb. Hemost. 76:835-856).Therefore, platelet ADP receptors are members of the family of P2receptors activated by purine and/or pyrimidine nucleotides (King, B.F., Townsend-Nicholson, A. & Burnstock, G. (1998) Trends Pharmacol. Sci.19:506-514).

Recent pharmacological data using selective antagonists suggests thatADP-dependent platelet aggregation requires activation of at least twoADP receptors (Kunapuli, S. P. (1998), Trends Pharmacol. Sci.19:391-394; Kunapuli, S. P. & Daniel, J. L. (1998) Biochem. J.336:513-523; Jantzen, H. M. et al. (1999) Thromb. Hemost. 81:111-117).One receptor appears to be identical to the cloned P2Y₁ receptor,mediates phospholipase C activation and intracellular calciummobilization and is required for platelet shape change. The secondplatelet ADP receptor important for aggregation mediates inhibition ofadenylyl cyclase. Molecular cloning of the gene or cDNA for thisreceptor (P2Y₁₂) has recently been reported (Hollopeter, G. et. al.(2001) Nature 409:202-207). Based on its pharmacological and signalingproperties this receptor has been previously termed P2Y_(ADP) (Fredholm,B. B. et al. (1997) TIPS 18:79-82), P2T_(AC) (Kunapuli, S. P. (1998),Trends Pharmacol. Sci. 19:391-394) or P2Y_(cyc) (Hechler, B. et al.(1998) Blood 92, 152-159).

Various directly or indirectly acting synthetic inhibitors ofADP-dependent platelet aggregation with antithrombotic activity havebeen reported. The orally active antithrombotic thienopyridinesticlopidine and clopidogrel inhibit ADP-induced platelet aggregation,binding of radiolabeled ADP receptor agonist 2-methylthioadenosine5′-diphosphate to platelets, and other ADP-dependent events indirectly,probably via formation of an unstable and irreversible acting metabolite(Quinn, M. J. & Fitzgerald, D. J. (1999) Circulation 100:1667-1667).Some purine derivatives of the endogenous antagonist ATP, e.g., AR-C(formerly FPL or ARL) 67085MX and AR-C69931MX, are selective plateletADP receptor antagonists which inhibit ADP-dependent plateletaggregation and are effective in animal thrombosis models (Humphries etal. (1995), Trends Pharmacol. Sci. 16, 179; Ingall, A. H. et al. (1999)J. Med. Chem. 42, 213-230). Novel triazolo[4,5-d]pyrimidine compoundshave been disclosed as P_(2T)-antagonists (WO 99/05144). Tricycliccompounds as platelet ADP receptor inhibitors have also been disclosedin WO 99/36425. The target of these antithrombotic compounds appears tobe the platelet ADP receptor mediating inhibition of adenylyl cyclase.

Despite these compounds, there exists a need for more effective plateletADP receptor inhibitors. In particular, there is a need for platelet ADPreceptor inhibitors having antithrombotic activity that are useful inthe prevention and/or treatment of cardiovascular diseases, particularlythose related to thrombosis.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds having theformula:

or a pharmaceutically acceptable salt thereof, wherein R represents H orC₁₋₆ alkyl; R¹ represents a member selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl and C₃₋₅ cycloalkyl-alkyl; R² represents amember selected from H, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, cyano and —C(O)R^(2a), wherein R^(2a) isselected from C₁₋₆ alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.

The letter L represents a 1 to 3 carbon linking group selected from—CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH(CH₃)— and —CH₂CH₂CH₂—. The symbol L¹represents a bond or —CH₂—. The symbol L² represents a bond, —NH— or—CH₂—.

The subscript t is an integer of from 0 to 1 when L² is a bond, and is 1when L² is —NH— or —CH₂—.

Ar¹ is an aromatic ring selected from benzene, pyridine and pyrimidine,each of which is optionally substituted with from 1-2 R³ substituents,wherein each R³ is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, —C(O)R^(3a),—O(CH₂)_(m)OR^(3b), —(CH₂)_(m)OR^(3b), —O(CH₂)_(m)N(R^(3b))₂ and—(CH₂)_(m)N(R^(3b))₂, wherein the subscript m is an integer of from 1 to3, each R^(3a) is independently selected from H, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, and each R^(3b) is independentlyselected from H, C₁₋₄ alkyl and C₁₋₄ alkanoyl, and optionally, twoR^(3b) groups attached to nitrogen are combined with the nitrogen atomto form an azetidine, pyrrolidine or piperidine ring.

Ar² is a 5-6 membered monocyclic or 9-10 membered fused-bicyclicaromatic ring system, optionally having from 1 to 3 heteroatoms selectedfrom N, O and S as ring vertices, the ring system being optionallysubstituted with from 1 to 3 R⁴ substituents, wherein each of the R⁴substituents is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino and —C(O)R^(4a), and eachR^(4a) is independently selected from H, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.

The present invention further provides pharmaceutical compositionscontaining one or more of the above compounds in admixture with apharmaceutically acceptable excipient.

In other aspects, the present invention provides methods of treatingthrombosis and thrombosis related conditions or disorders wherein acompound having the formula above is administered to a patient in needof such treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 provide structures of selected and preferred compounds of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁-₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group is one having one or more double bonds.Similarly, the term “alkynyl” refers to an unsaturated alkyl grouphaving one or more triple bonds. Examples of such unsaturated alkylgroups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl”refers to hydrocarbon rings having the indicated number of ring atoms(e.g., C₃₋₆cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. When “cycloalkyl” is used incombination with “alkyl”, as in C₃₋₅ cycloalkyl-alkyl, the cycloalkylportion is meant to have from three to five carbon atoms, while thealkyl portion is an alkylene moiety having from one to three carbonatoms (e.g., —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. For brevity, the termC₁₋₆alkylamino is meant to include straight chain, branched or cyclicalkyl groups or combinations thereof, such as methyl, ethyl,2-methylpropyl, cyclobutyl and cyclopropylmethyl.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁-₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. Exemplary aryl groups are phenyl, naphthyl, biphenyl and thelike. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of theabove noted aryl and heteroaryl ring systems are selected from the groupof acceptable substituents described below.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

DESCRIPTION OF THE EMBODIMENTS

Compounds

In view of the above, the present invention provides, in one aspect,compounds having the formula:

or a pharmaceutically acceptable salt thereof, wherein R represents H orC₁₋₆ alkyl, preferably H or CH₃, and more preferably H. The symbol R¹represents a member selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₅cycloalkyl and C₃₋₅ cycloalkyl-alkyl, more preferably H or C₁₋₄ alkyl,still more preferably H or CH₃, and most preferably H. The symbol R²represents a member selected from H, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, cyano and —C(O)R^(2a),wherein R^(2a) is selected from C₁₋₆ alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.More preferably R² is selected from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂. Still more preferably, R² ishalogen and is attached to the 5-position of the thienyl ring.

The letter L represents a 1 to 3 carbon linking group selected from—CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH(CH₃)— and —CH₂CH₂CH₂—. Preferably, Lis selected from —CH₂—, —CH(CH₃)— and —CH₂CH₂—. More preferably, L isselected from —CH₂— and —CH(CH₃)—. The symbol L¹ represents a bond or—CH₂—, preferably a bond. The symbol L² represents a bond, —NH— or—CH₂—, preferably a bond or —NH—. In further preferred embodiments, L²is —NH—.

The subscript t is an integer of from 0 to 1 when L² is a bond, and is 1when L² is —NH— or —CH₂—.

Ar¹ is an aromatic ring selected from benzene, pyridine and pyrimidine,each of which is optionally substituted with from 1-2 R³ substituents,wherein each R³ is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, —C(O)R^(3a),—O(CH₂)_(m)OR^(3b), —(CH₂)_(m)OR^(3b), —O(CH₂)_(m)N(R^(3b))₂ and—(CH₂)_(m)N(R^(3b))₂, wherein the subscript m is an integer of from 1 to3, each R^(3a) is independently selected from H, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, and each R^(3b) is independentlyselected from H, C₁₋₄ alkyl and C₁₋₄ alkanoyl, and optionally, twoR^(3b) groups attached to nitrogen are combined with the nitrogen atomto form an azetidine, pyrrolidine or piperidine ring. Preferably, eachR³ is independently selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and —O(CH₂)_(m)N(R^(3b))₂ whereinthe subscript m is 1 or 2 and each R^(3b) is independently selected fromH, C₁₋₄ alkyl and C₁₋₄ alkanoyl.

Ar² is a 5-6 membered monocyclic or 9-10 membered fused-bicyclicaromatic ring system, optionally having from 1 to 3 heteroatoms selectedfrom N, O and S as ring vertices, the ring system being optionallysubstituted with from 1 to 3 R⁴ substituents, wherein each of the R⁴substituents is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino and —C(O)R^(4a), and eachR^(4a) is independently selected from H, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy and (C₁₋₆ alkyl)₀₋₂ amino. In one group of preferred embodiments,Ar² is benzene or naphthalene, each of which is optionally substitutedwith from 1 to 3 R⁴ substituents. In another group of preferredembodiments, Ar² is furan, thiophene, thiazole, oxazole, thiadiazole,imidazole, pyrazole, pyridine or pyrimidine, each of which is optionallysubstituted with from 1 to 3, or more preferably 1 to 2 R⁴ substituents.In still another group of preferred embodiments, Ar² is benzothiophene,indole, quinoline, isoquinoline, benzofuran, benzimidazole, benzoxazoleor benzothiazole, each of which is optionally substituted with from 1 to3, or more preferably 1 to 2 R⁴ substituents.

In Formula I above, the group Ar²-L-N(R¹)— is preferably attached to the6- or 7-position of the 2,4-dioxo-quinazoline ring system, numbered asshown below:

More preferably, the group Ar²-L-N(R¹)— is attached to the 7-position ofthe 2,4-dioxo-quinazoline ring system.

Within the descriptions above are a number of preferred embodiments. Inone group of preferred embodiments, R¹ is H or C₁₋₄ alkyl; L is —CH₂—,—CH(CH₃)— or —CH₂CH₂—; L¹ is a bond and R² is halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH or —CONH₂.

In another group of preferred embodiments, Ar¹ is a benzene ring,optionally substituted with 1-2 R³ substituents. In yet another group ofpreferred embodiments, Ar¹ is a pyridine ring, optionally substitutedwith 1-2 R³ substituents. In still another group of preferredembodiments, Ar¹ is a pyrimidine ring, optionally substituted with 1-2R³ substituents. Within each of these groups of embodiments, one groupof further preferred compounds are those in which Ar² is benzene ornaphthalene, each of which is optionally substituted with from 1 to 3 R⁴substituents. Still further preferred in this group of embodiments arethose compounds in which R¹ is H or C₁₋₄ alkyl; L is —CH₂—, —CH(CH₃)— or—CH₂CH₂—; L¹ is a bond and R² is halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, —CN, —C≡CH or —CONH₂.

In a related group of preferred embodiments, Ar¹ is a benzene ring,optionally substituted with 1-2 R³ substituents and Ar² is furan,thiophene, thiazole, oxazole, thiadiazole, imidazole, pyrazole,pyridine, pyrimidine, benzothiophene, indole, quinoline, isoquinoline,benzofuran, benzimidazole, benzoxazole or benzothiazole, each of whichis optionally substituted with from 1 to 3 R⁴ substituents. In one groupof embodiments, Ar² is a monocyclic ring selected from furan, thiophene,thiazole, oxazole, thiadiazole, imidazole, pyrazole, pyridine andpyrimidine. In another group of embodiments, Ar² is a fused bicyclicring system selected from benzothiophene, indole, quinoline,isoquinoline, benzofuran, benzimidazole, benzoxazole and benzothiazole.One of skill in the art will appreciate that attachment to the remainderof the compound can be through any available valence site on the ring orring system. For example, “pyridine” is meant to include 2-pyridyl,3-pyridyl and 4-pyridyl moieties. Similarly, attachment for one of thefused ring systems can be through either of the two rings. For example,“benzothiazole” is meant to include 2-benzothiazolyl as well as5-benzothiazolyl and the like. Preferred attachment sites are thoseprovided in the Examples and Figures herein. Still further preferred ineach of these groups of embodiments are those compounds in which R¹ is Hor C₁₋₄ alkyl; L is —CH₂—, —CH(CH₃)— or —CH₂CH₂—; L¹ is a bond and R² ishalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH or —CONH₂.

One group of particularly preferred embodiments, compounds of thepresent invention are represented by formula Ia:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to 2. The remaining groups R¹, R², R³ and R⁴ have the meaningsprovided with respect to formula I above. Further preferred for thecompounds of formula Ia are those in which R¹ is H; R² is selected fromhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂;each R³, when present is independently selected from C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and eachR⁴, when present is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆alkyl)₀₋₂ amino. Still further preferred are those compounds of formulaIa wherein R² is halogen and is attached to the 5-position of thethienyl ring; and each R⁴ when present is independently selected fromhalogen, cyano and C₁₋₆ alkyl.

Another group of particularly preferred compounds of the presentinvention are represented by formula Ib:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to 2. The remaining groups Ar², R¹, R², R³ and R⁴ have themeanings provided with respect to formula I above. In one group ofpreferred embodiments, for the compounds of formula Ib, Ar² is selectedfrom furan, thiophene, thiazole, oxazole, thiadiazole, imidazole,pyrazole, pyridine and pyrimidine. In another group of preferredembodiments, Ar² is a fused bicyclic ring system selected frombenzothiophene, indole, quinoline, isoquinoline, benzofuran,benzimidazole, benzoxazole and benzothiazole. Further preferred for eachgroup of embodiments of formula Ib are those in which R¹ is H; R² isselected from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN,—C≡CH and —CONH₂; each R³, when present is independently selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and eachR⁴, when present is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆alkyl)₀₋₂ amino. Still further preferred are those compounds of formulaIb wherein R² is halogen and is attached to the 5-position of thethienyl ring; and each R⁴ when present is selected from halogen, cyanoand C₁₋₆ alkyl.

Another group of particularly preferred compounds of the presentinvention are represented by formula Ic:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to 2. The remaining groups Ar², R¹, R², R³ and R⁴ have themeanings provided with respect to formula I above. In one group ofpreferred embodiments, for the compounds of formula Ic, Ar² is selectedfrom furan, thiophene, thiazole, oxazole, thiadiazole, imidazole,pyrazole, pyridine and pyrimidine. In another group of preferredembodiments, Ar² is a fused bicyclic ring system selected frombenzothiophene, indole, quinoline, isoquinoline, benzofuran,benzimidazole, benzoxazole and benzothiazole. Further preferred for eachgroup of embodiments of formula Ic are those in which R¹ is H; R² isselected from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN,—C≡CH and —CONH₂; each R³, when present is independently selected fromC₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and eachR⁴, when present is independently selected from halogen, cyano, hydroxy,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆alkyl)₀₋₂ amino. Still further preferred are those compounds of formulaIb wherein R² is halogen and is attached to the 5-position of thethienyl ring; and each R⁴ when present is selected from halogen, cyanoand C₁₋₆ alkyl.

Another group of particularly preferred compounds of the presentinvention are represented by formula Id:

wherein the subscript n1 represents an integer of from 0 to 2, and R¹ isa member selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl andC₃₋₅ cycloalkyl-alkyl. The remaining groups R² and R³ have the meaningsprovided with respect to formula I above. In preferred embodiments, R²is selected from halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN,—C≡CH and —CONH₂; and each R³, when present is independently selectedfrom C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b)and —O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and eachR^(3b) is independently selected from the group consisting of H, C₁₋₄alkyl and C₁₋₄ alkanoyl. Still further preferred are those compounds offormula Id wherein R² is halogen and is attached to the 5-position ofthe thienyl ring.

A number of specific compounds are among the most preferred embodimentsfor the compounds of formula I, and are provided in FIGS. 1-3.

Preparation of the Compounds of Formula I

Scheme 1 illustrates a method of preparing certain compounds of FormulaI wherein R¹, R², Ar¹ and Ar² are described above.

A compound of Formula I can be prepared by reacting4-tert-butoxycarbonylamino-2-nitro-benzoic acid methyl ester, preparedby previously described methods (see published patent applicationUS2002077486) and substituted arylalkyl halides in the presence of abase such as potassium carbonate, cesium carbonate or sodium hydride ina inert solvent such as DMF of THF to obtain a compound 2. The nitrogroup of compound 2 can be reduced by procedures known to one skilled inthe art to yield aniline 3. For example, a method of nitro groupreduction can be carried out by hydrogenation. The hydrogenation iscarried out with a suitable catalyst (e.g., 10% Pd/C or Pt(s)/C) underhydrogen and in an appropriate solvent, typically in an alcohol,preferably ethanol at room temperature. Treating compound 3 withappropriately substituted aryl or heteroaryl isocyante (Method A)provides intermediate urea 4. Alternatively, urea 4 can be formed bytreating compound 3 with triphosgene in the presence of a base such astriethylamine or diisopropylethylamine in an inert solvent such as THF,dichloromethane and MeCN at appropriate temperature, preferably at 20C.°, followed by substituted aryl or heteroaryl amines (Method B). Urea4, prepared by Method A or Method B typically without furtherpurification can be subjected to thermal or based induced ring closureto provide quinazolindione 5. The nitro group of compound 5 can bereduced by procedures known to one skilled in the art to yield freeamino group. For example, a method of reduction can be carried out byhydrogenation, with a suitable catalyst (e.g., 10% palladium on carbon)in an appropriate solvent, typically an alcohol. The formation ofsulfonylurea linkage can be accomplished by treating the reduced productaniline 6 with a pre-mixed solution of substitutedthiophene-2-sulfonamide, N,N′-disuccinimidyl carbonate andtetramethylguanidine in dichloromethane, followed by treatment with TFAin dichloromethane at room temperature to afford the sulfonylurea ofFormula I. Alternatively, the sulfonylurea linkage can be formed byreacting the aniline 6 and 5-Chloro-thiophene-2-sulfonamideethylcarbonate in toluene.

Scheme 2 illustrates an alternative method of preparing compounds ofFormula I wherein R¹, R², Ar¹ and Ar² are described above.

A compound of Formula I can be prepared by reducing4-tert-butoxycarbonylamino-2-nitro-benzoic acid methyl ester to aniline9 by standard hydrogenation with 10% Pd/C in ethyl acetate. Treatingcompound 9 with appropriately substituted aryl or heteroaryl isocyante(Method A) provides intermediate urea 10. Alternatively, urea 10 can beformed by treating compound 9 with triphosgene in the presence of a basesuch as triethylamine or diisopropylethylamine in an inert solvent suchas THF, dichloromethane and MeCN at appropriate temperature, preferablyat 20° C., followed by substituted aryl or heteroaryl amines (Method B).Urea 10, prepared by Method A or Method B typically without furtherpurification can be subjected to thermal or based induced ring closureto provide quinazolindione 11. The nitro group of compound 11 can bereduced by procedures known to one skilled in the art to yield freeamino group. For example, a method of reduction can be carried out byhydrogenation, with a suitable catalyst (e.g., 10% palladium on carbon)in an appropriate solvent, typically ethyl acetate, methanol,dimethylformamide or a mixture of them. The preparation of sulfonylurea13 can be accomplished by treating aniline 12 with a pre-mixed solutionof substituted thiophene-2-sulfonamide, N,N′-disuccinimidyl carbonateand tetramethylguanidine in dichloromethane, followed by treatment withTFA in dichloromethane at room temperature to afford the sulfonylurea ofFormula I. Alternatively, compound 13 can be prepared by reacting theaniline 6 and 5-chloro-thiophene-2-sulfonamide ethylcarbonate in hottoluene, dioxane or acetonitrile. Treatment of compound 13 using a 1:1mixture of dichloromethane and trifluoroacetic acid, or using thecommercial 4N HCl solution in dioxane, in ice bath yields aniline 14.Reductive amination of aniline 14 with an aldehyde, sodiumcyanoborohydride and acetic acid in methyl sulfoxide gives targetcompound 15.

A compound of Formula I, wherein acylsulfonamide is the linker, can beprepared by treating compound 3 with appropriately substituted aryl orheteroaryl isocyante (Scheme 3, Method A) to provide intermediate urea16. Alternatively, urea 16 can be formed by treating compound 3 withtriphosgene in the presence of a base such as triethylamine ordiisopropylethylamine in an inert solvent such as THF, dichloromethaneand MeCN at appropriate temperature, preferably at 20° C., followed bysubstituted aryl or heteroaryl amines (Method B). Urea 16, prepared byMethod A or Method B typically without further purification can besubjected to thermal or based induced ring closure to providequinazolindione 17. The ester of compound 17 can be converted to thecarboxylic acid by treatment with lithium hydroxide in an appropriatesolvent or solvent mixture such as dioxane/water or THF/water.Conversion of the carboxylic acid to acyl sulfonamide 19 is accomplishedby treatment with DIC, DMAP and a suitably substituted sulfonamide ineither dichloromethane or DMF as the solvent. Treatment of the Bocprotected analog with acid, either 50% TFA in dichloromethane or 4M HClin dioxane, affords the acylsulfonamide of Formula I.

Compositions

In another aspect of the invention, pharmaceutical compositions areprovided in which compounds of formulae I, Ia, Ib, Ic or Id, alone or incombination, are combined with a pharmaceutically acceptable carrier.Preferred compounds for use in the compositions of the present inventionare those compounds identified above as specific or preferredembodiments.

The pharmaceutical compositions of the invention may be in the form ofsolutions or suspensions. In the management of thrombotic disorders thecompounds or pharmaceutical compositions of the invention may also be insuch forms as, for example, tablets, capsules or elixirs for oraladministration, suppositories, sterile solutions or suspensions orinjectable administration, and the like, or incorporated into shapedarticles.

Typical adjuvants which may be incorporated into tablets, capsules andthe like include, but are not limited to, binders such as acacia, cornstarch or gelatin, and excipients such as microcrystalline cellulose,disintegrating agents like corn starch or alginic acid, lubricants suchas magnesium stearate, sweetening agents such as sucrose or lactose, orflavoring agents. When a dosage form is a capsule, in addition to theabove materials it may also contain liquid carriers such as water,saline, or a fatty oil. Other materials of various types may be used ascoatings or as modifiers of the physical form of the dosage unit.Sterile compositions for injection can be formulated according toconventional pharmaceutical practice. For example, dissolution orsuspension of the active compound in a vehicle such as an oil or asynthetic fatty vehicle like ethyl oleate, or into a liposome may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice.

Additionally, dosage formulations of compounds of formulae I, Ia, Ib, Icor Id, or pharmaceutical compositions containing a compound of theinvention, to be used for therapeutic administration must be sterile.Sterility can be readily accomplished by filtration through sterilemembranes such as 0.2 micron membranes, or by other conventionalmethods. Formulations typically will be stored in a solid form,preferably in a lyophilized form. While the preferred route ofadministration is orally, the dosage formulations of compounds offormulae I, Ia, Ib, Ic or Id, or pharmaceutical compositions of theinvention may also be administered by injection, intravenously (bolusand/or infusion), subcutaneously, intramuscularly, colonically,rectally, nasally, transdermally or intraperitoneally. A variety ofdosage forms may be employed as well including, but not limited to,suppositories, implanted pellets or small cylinders, aerosols, oraldosage formulations and topical formulations such as ointments, dropsand dermal patches. The compounds of formulae I, Ia, Ib, Ic or Id, andpharmaceutical compositions of the invention may also be incorporatedinto shapes and articles such as implants which may employ inertmaterials such biodegradable polymers or synthetic silicones as, forexample, SILASTIC, silicone rubber or other polymers commerciallyavailable. The compounds and pharmaceutical compositions of theinvention may also be provided in the form of liposome delivery systems,such as small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from a variety oflipids, such as cholesterol, stearylamine or phosphatidylcholines, usedmethods well known to one of skill in the art.

Methods of Treatment/Administration

In yet another aspect, the present invention provides methods forpreventing or treating thrombosis in a mammal by administering to themammal a therapeutically effective amount of a compound of formulae I,la, Ib, Ic or Id, alone or as part of a pharmaceutical composition ofthe invention as described above. Compounds of formulae I, Ia, Ib, Ic orId, and pharmaceutical compositions of the invention containing acompound of formulae I, Ia, Ib, Ic or Id, of the invention are suitablefor use alone or as part of a multi-component treatment regimen for theprevention or treatment of cardiovascular diseases, particularly thoserelated to thrombosis. For example, a compound or pharmaceuticalcomposition of the invention may be used as a drug or therapeutic agentfor any thrombosis, particularly a platelet-dependent thromboticindication, including, but not limited to, acute myocardial infarction,unstable angina, chronic stable angina, transient ischemic attacks,strokes, peripheral vascular disease, preeclampsia/eclampsia, deepvenous thrombosis, embolism, disseminated intravascular coagulation andthrombotic cytopenic purpura, thrombotic and restenotic complicationsfollowing invasive procedures, e.g., angioplasty, carotidendarterectomy, post CABG (coronary artery bypass graft) surgery,vascular graft surgery, stent placements and insertion of endovasculardevices and protheses.

Compounds and pharmaceutical compositions of the invention may also beused as part of a multi-component treatment regimen in combination withother therapeutic or diagnostic agents in the prevention or treatment ofthrombosis in a mammal. In certain preferred embodiments, compounds orpharmaceutical compositions of the invention may be coadministered alongwith other compounds typically prescribed for these conditions accordingto generally accepted medical practice such as anticoagulant agents,thrombolytic agents, or other antithrombotics, including plateletaggregation inhibitors, tissue plasminogen activators, urokinase,prourokinase, streptokinase, heparin, aspirin, or warfarin. Still otheragents that can be administered with the compounds of the presentinvention include antiplatelet compounds, fibrinolytics,anti-inflammatory compounds, cholesterol-lowering agents,blood-pressure-lowering agents and serotonin blockers. Suitableantiplatelet compounds include GPIIB-IIIa antagonists, aspirin,phosphodiesterase III inhibitors and thromboxane A2 receptorantagonists. Suitable anticoagulants include thrombin inhibitors,coumadin (Warfarin), heparin and Lovenox®. Suitable anti-inflammatorycompounds include non-steroidal anti-inflammatory agents,cyclooxygenase-2 inhibitors and rheumatoid arthritis agents.Coadministrations of these agents with the compounds of the inventionmay also allow for application of reduced doses of the thrombolyticagents and therefore minimize potential hemorrhagic side-effects.Compounds and pharmaceutical compositions of the invention may also actin a synergistic fashion to prevent reocclusion following a successfulthrombolytic therapy and/or reduce the time to reperfusion.

In related methods, the compounds of the invention are useful for theprevention of a secondary ischemic event. In these methods, compounds ofthe invention or their pharmaceutical compositions are administered to apatient who has suffered a primary ischemic event in an amountsufficient to prevent or reduce the likely occurrence of a secondaryevent. Generally, the primary and/or secondary ischemic event isselected from myocardial infraction, stable or unstable angina, acutereocclusion after percutaneous transluminal coronary angioplasty,restenosis, thrombotic stroke, transient ischemic attack, reversibleischemic neurological deficit and intermittent claudication.

The compounds and pharmaceutical compositions of the invention may beutilized in vivo, ordinarily in mammals such as primates, (e.g.,humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or invitro. The biological properties, as defined above, of a compound or apharmaceutical composition of the invention can be readily characterizedby methods that are well known in the art such as, for example, by invivo studies to evaluate antithrombotic efficacy, and effects onhemostasis and hematological parameters.

Subjects (typically mammalian) in need of treatment using the compoundsor pharmaceutical compositions of the invention may be administereddosages that will provide optimal efficacy. The dose and method ofadministration will vary from subject to subject and be dependent uponsuch factors as the type of mammal being treated, its sex, weight, diet,concurrent medication, overall clinical condition, the particularcompound of formulae I, Ia, Ib, Ic or Id employed, the specific use forwhich the compound or pharmaceutical composition is employed, and otherfactors which those skilled in the medical arts will recognize.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound or pharmaceuticalcomposition of the invention, individual determinations may be made todetermine the optimal dosage required. The range of therapeuticallyeffective dosages will be influenced by the route of administration, thetherapeutic objectives and the condition of the patient. For injectionby hypodermic needle, it may be assumed the dosage is delivered into thebodily fluids. For other routes of administration, the absorptionefficiency must be individually determined for each compound by methodswell known in pharmacology. Accordingly, it may be necessary for thetherapist to titer the dosage and modify the route of administration asrequired to obtain the optimal therapeutic effect.

The determination of effective dosage levels, that is, the dosage levelsnecessary to achieve the desired result, i.e., platelet ADP receptorinhibition, will be readily determined by one skilled in the art.Typically, applications of a compound or pharmaceutical composition ofthe invention are commenced at lower dosage levels, with dosage levelsbeing increased until the desired effect is achieved. The compounds andcompositions of the invention may be administered orally in an effectiveamount within the dosage range of about 0.01 to 1000 mg/kg in a regimenof single or several divided daily doses. If a pharmaceuticallyacceptable carrier is used in a pharmaceutical composition of theinvention, typically, about 5 to 500 mg of a compound of formulae I, Ia,Ib, Ic or Id, is compounded with a pharmaceutically acceptable carrieras called for by accepted pharmaceutical practice including, but notlimited to, a physiologically acceptable vehicle, carrier, excipient,binder, preservative, stabilizer, dye, flavor, etc. The amount of activeingredient in these compositions is such that a suitable dosage in therange indicated is obtained.

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

EXAMPLES

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Example 1 2-Amino-4-(benzyl-tert-butoxycarbonyl-amino)-benzoic acidmethyl ester

To a suspension of CsCO₃ (4.9 g, 15 mmoles) and(4-tert-Butoxycarbonylamino-2-nitro-benzoic acid methyl ester (2.96 g,10 mmoles) in anhydrous DMF (100 mL) was added benzyl bromide (2.57 g,15 mmoles) and the resulting mixture was stirred at room temperature for12 hrs. The reaction mixture was filtered, concentrated, diluted withethyl acetate, and washed with 5% citric acid, saturated NaHCO₃ solutionand water. The organic phase was hydrogenated over 10% Pd/C in EtOAc.After 12 hr, the mixture was filtered through a celite pad, and thefiltrate was concentrated in vacuo to give a crude oil which waspurified by column chromatography to furnish the desired product as anoff-white solid (2.05 g, 57% yield). ES⁺ MS showed 357 m/z, the correctmass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed β=1.34 (s, 9H),3.71 (s, 3H), 4.74 (s, 2H), 6.39 (d, J=9 Hz, 1H), 6.62 (s, 1+2H), 7.19(d, J=7 Hz, 2H), 7.24 (d, J=7 Hz, 1H), 7.32 (dd, J₁=J₂=7 Hz, 2H).

Example 2[3-(4-Amino-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl]-benzyl-carbamicacid tert-butyl ester

A solution of 2-Amino-4-(benzyl-tert-butoxycarbonyl-amino)-benzoic acidmethyl ester (890 mg, 2.5 mmoles) and 4-nitrophenyl isocyanate (0.45 g,2.75 mmoles) in the mixture of toluene (8 mL) and DMF (15 mL) was heatedto 90° C. and stirred for 24 hrs. After filtration, the intermediate inthe solution was hydrogenated over 10% Pd/C in EtOAc. When the reactioncompleted (12-24 hrs), the mixture was filtered through a celite pad,and the filtrate was concentrated in vacuo to give a crude solid whichwas purified by high pressure liquid chromatography to furnish compound6 as a off-white solid (813 mg). ES⁺ MS showed 459 m/z, the correct massfor the product. ¹H NMR (400 MHz, DMSO-d₆) showed β=1.40 (s, 9H), 4.90(s, 2H), 5.19 (s, 2H), 6.55 (d, J=8 Hz, 2H), 6.82 (d, J=8 Hz, 2H), 7.08(s, 1H), 7.09 (d, J=8 Hz, 1H), 7.19 (d, J=7 Hz, 2H), 7.24 (d, J=7 Hz,1H), 7.32 (dd, J₁=J₂=7 Hz, 2H), 11.31 (s, 1H).

Example 35-Chloro-N-[({4-(7-Benzylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-phenylamino)carbonyl]thiophene-2-sulfonamide

To a suspension of[3-(4-Amino-phenyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl]-benzyl-carbamicacid tert-butyl ester (92 mg, 0.2 mmol) and5-Chloro-thiophene-2-sulfonamide ethylcarbonate (60 mg, 0.22 mmol) intoluene (8 mL) was heated at reflux for 3 hours. The reaction mixturewas concentrated and dried under vacuum. The residue was treated with90% TFA with water for 20 minutes. After TFA was evaporated,purification with high pressure liquid chromatography furnished acolorless powder. ES⁺ MS showed 582 m/z and ES⁻ MS 580 m/z, the correctmass for the product. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 4.31 (d, J=6Hz, 2H), 6.18 (s, 1H), 6.48 (d, J=9 Hz, 1H), 7.08 (d, J=9 Hz, 2H), 7.22(m, 2H), 7.32 (m, 4H), 7.41 (m, 3H), 7.55 (d, J=9 Hz, 1H), 7.60 (m, 1H),9.06 (s, 1H), 11.05 (s, 1H).

Example 4 tert-butyl4-fluorobenzyl(3-(4-amino-3-methylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)carbamate

A solution of 3-methyl-4-nitroaniline (231 mg, 1.52 mmol) andtriethylamine (0.42 mL, 3.04 mmol) in dichloromethane (10 mL) was addedslowly to a suspension of disuccinylcarbonate (389 mg, 1.52 mmol) indichloromethane (10 mL) during which time the suspension becamehomogeneous. The reaction was stirred until all starting aniline wasconsumed, then treated with the aniline prepared from 4-fluorobenylbromide using procedure described in example 1 (300 mg, 1.17 mmol) andstirred at rt overnight. The reaction mixture was concentrated todryness, then diluted with DMF and heated to 90° C. for 4 hrs at whichtime it was cooled to rt, diluted with water which was then extratedtwice with ethyl acetate and the combined organic layers then dried overmagnesium sulfate. After concentration, the crude product was purifiedby silica gel chromatography. The resulting yellow solid was thenreduced as described in Example 2 affording 10 mg of the desired aniline(10% yield, 2 steps). ES⁺ MS showed 491 m/z, the correct mass for theproduct. ¹H NMR (400 MHz, CDCl₃) showed δ=1.40 (s, 9H), 2.20 (s, 3H),4.83 (s, 2H), 6.73 (m, 1H), 6.86 (m, 7H), 7.13 (m, 2H), 7.99 (m, 2H),10.08 (s, 1H).

Example 51-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-3-(5-chlorothiophen-2-ylsulfonyl)urea

The aniline from example 4 was converted to the title compound using theexperimental procedure described in example 3. ES⁺ MS showed 614 m/z,the correct mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showedδ=2.23 (s, 3H), 4.39 (s, 2H), 6.16 (s, 1H), 6.54 (d, 1H), 7.04 (m, 5H),7.37 (m, 2H), 7.69 (m, 3H).

Example 6 tert-butyl4-fluorobenzyl(3-(4-amino-3,5-dimethylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)carbamate

A solution of 3,5-dimethyl-4-nitroaniline (100 mg, 0.60 mmol) in THF (10mL) was treated with 10% Palladium on carbon (Degussa, 10 mg) andstirred under an atmosphere of H₂ for five hours at which time it wasfiltered, concentrated and submitted to the conditions described formethod B affording the title compound as an off-white solid (89 mg, 29%yield for 2 steps). ES⁺ MS showed 505 m/z, the correct mass for theproduct. ¹H NMR (400 MHz, DMSO-d₆) showed δ=1.41 (s, 9H), 4.85 (s, 2H),6.83 (s, 2H), 6.98 (m, 4H), 7.17 (m, 2H), 8.00 (d, 1H), 9.50 (br s, 1H).

Example 71-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2,6-dimethylphenyl)-3-(5-chlorothiophen-2-ylsulfonyl)urea

Disuccinylcarbonate (290 mg, 1.13 mmol) was suspended in dichloromethane(5 mL) and then treated with a solution of5-chloro-2-thiophenesulfonamide (210 mg, 1.05 mmol) andtetramethylguanidine (0.22 mL, 1.74 mmol) in 5 mL dichloromethane duringwhich time the reaction became homogeneous. The reaction mixture wasstirred at rt overnight, then the solvent removed in vacuo and theresidue suspended in acetonitrile and transferred to a flask containingthe aniline from example 6 (440 mg, 0.87 mmol). The mixture was refluxedovernight, then cooled and diluted with aq ammonium chloride which wasthen extrated thrice with dichloromethane and concentrated to dryness.The crude producted was diluted with dichloromethane (10 mL) and treatedwith trifluoroacetic acid (10 mL) and stirred for 1 hr during which timea flocculant precipitate formed. The solvent was removed and the residuediluted with a small amount of acetonitrile and water resulting in awhite ppt which was filtered and dried affording the desired product asa fluffy white solid. ES⁻ MS showed 626 m/z, the correct mass for theproduct. ¹H NMR (400 MHz, DMSO-d₆) showed δ=2.03 (s, 6H), 4.29 (s, 2H),6.18 (s, 1H), 6.48 (d, 1H), 6.90 (s, 2H), 7.19 (t, 2H), 7.26 (s, 1H),7.38 (m, 3H), 7.57 (d, 1H), 7.65 (s, 1H), 8.21 (s, 1H), 11.09 (s, 1H).

Similarly, following the procedure described in Examples 1-3, butreplacing benzyl bromide and 4-nitrophenyl isocyanate with otherappropriate arylalkyl, heteroarylalkyl bromides and aryl isocyanates,and utilizing the modifications known to those skilled in the art, theadditional compounds of the general Formula I were prepared (see Table1): TABLE 1 Example Structure ES-MS(M − H)⁺ = 8

695 9

651 10

740 11

607 12

614 13

605 14

605 15

628 16

595 17

672 18

598 19

594 20

636 21

598 22

594 23

598 24

614 25

616 26

634 27

657 28

657 29

647 30

612 31

671 32

638 33

624 34

594 35

624 36

581 37

594 38

630 39

614 40

648 41

610 42

594 43

612 44

599

Example 45 2-Amino-4-(tert-butoxycarbonylamino)-benzoic acid methylester

To a solution of 4-(tert-butoxycarbonylamino)-2-nitro-benzoic acidmethyl ester (7.0 g, 23.6 mmoles) in 400 mL ethyl acetate was added 1.0g 10% Pd/C. The reaction mixture was subjected to hydrogenation using aballoon for 24-36 hrs or until the reaction was complete as monitored byHPLC. The mixture was filtered through a celite bed, and the solid cakewas thoroughly washed by ethyl acetate. The filtrate was concentrated invacuo to dryness to afford the title compound (6.3 g, 99%). ES⁺ MSshowed 267 m/z, the correct mass for the product.

Example 46 tert-Butyl3-(4-aminophenyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-7-ylcarbamate

A solution of 2-amino-4-(tert-butoxycarbonylamino)-benzoic acid methylester (6.3 g, 23.6 mmol) and 4-nitrophenyl isocyanate (7.8 g, 47.4mmoles) in 100 mL dry dimethylformamide was stirred at room temperaturefor 20 hrs. To it was then added diisopropylamine (8.2 mL, 47.4 mmol),and the reaction mixture was heated in 80° C. bath for 2 hrs. It wascooled to room temperature and the solid precipitates were filtered off.The dimethylformamide filtrate was concentrated in vacuo to evaporatethe solvent. To the residue was added 400 mL dichloromethane. Afterstirred and swirled, the solid was isolated by filtration. This solidwas then dissolved in 100 mL dimethylformamide and 200 mL methanol. Toit was added 1.0 g 10% Pd/C, and the mixture was subjected to standardhydrogenation using a balloon for 20 hrs. It was filtered through acelite bed. The filtrate was concentrated in vacuo and purified usingflash column to afford the title compound (4.1 g, 44%). ES⁺ MS showed397 m/z, the correct mass for the product.

Example 475-Chloro-N-[(4-(7-amino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenylamino)carbonyl]thiophene-2-sulfonamide

A mixture of tert-Butyl3-(4-aminophenyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-7-ylcarbamate(4.0 g, 10 mmol) and 5-chlorothiophene-2-sulfonamide ethylcarbonate (3.0g, 11 mmol) in 200 mL toluene was refluxed for 16 hrs. It wasconcentrated in vacuo. At room temperature, to this residue was addedcommercial 4N HCl dioxane (20 mL). The mixture was stirred for 1 h andconcentrated in vacuo. The solid was triturated with dichloromethane.The solid was isolated by filtration and dried in vacuo. It was thetitle compound (2.6 g, 53%). ES⁺ MS showed 492 m/z and ES⁻ MS 490 m/z,the correct mass for the product.

Example 485-Chloro-N-[(4-(7-(thiophen-2-yl)-amino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenylamino)carbonyl]thiophene-2-sulfonamide

Compound5-Chloro-N-[(4-(7-amino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenylamino)carbonyl]thiophene-2-sulfonamide(40 mg, 0.08 mmol) was dissolved in methyl sulfoxide (0.5 mL). To it wasadded acetic acid (1.0 mL) and thiophene-2-carbaldehyde (18 mg, 0.16mmol). The mixture was stirred for 15 minutes at room temperature. To itwas then added sodium cyanoborohydride (21 mg, 0.32 mmol). The mixturewas stirred for 30 minutes and quenched with water (2 mL). The reactionmixture was then directly subjected to preparative HPLC purification toyield the title compound (26 mg, 55%). ES⁺ MS showed 588 m/z and ES⁻ MS586 m/z, the correct mass for the product.

Similarly, following the procedure described in Examples 28-31, butreplacing thiophene-2-carbaldehyde with other appropriate carbaldehydes,and utilizing the modifications known to those skilled in the art, theadditional compounds of the general Formula I were prepared (see Table2). TABLE 2 Example Structure ES-MS(M − H)⁻ = 49

600 50

614 51

620 52

664 53

600 54

620 55

664 56

600 57

586 58

600 59

620 60

664 61

587 62

601 63

621 64

665 65

615 66

587 67

587 68

588 69

570 70

570 71

584 72

604 73

648 74

648 75

615 76

570 77

584 78

570 79

584 80

584 81

584 82

570 83

598 84

598 85

584 86

615 87

599 88

581 89

581 90

631 91

619 92

636 93

636 94

637 95

586 96

560 97

612 98

612 99

612 100

612 101

616 102

616 103

616 104

616

Example 1054-(7-(tert-butoxycarbonyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzoicacid

Step 1:

The aniline prepared from 4-fluorobenyl bromide using proceduredescribed in example 1 (600 mg, 1.6 mmol) was diluted with DMF (6 mL)then treated with 4methyl 4-isocyanatobenzoate (430 mg, 2.4 mmol) andstirred at 90° C. overnight. Triethylamine (0.33 mL, 2.3 mmol) was addedand the mixture heated for an additional 3 hrs at which time allmaterial had cyclized to the desired product. The reaction was cooled,diluted with water and extracted twice with ethyl acetate and once withdichloromethane, the combined organic phases then dried over magnesiumsulfate. After concentration the crude residue was purified by silicagel chromatography affording the desired producted (539 mg, 65%)contaminated with a small amount of the symmetrical urea derived fromthe isocyanate.

Step 2:

The mixture was then diluted with 5 mL of THF and treated with aq LiOH(1M, 2 mL, 2 mmol). Acetonitrile was added dropwise to the biphasicmixture until homogeneous. After stirring overnight the mixture wasacidified with 1 M HCl to pH=3 then extrated with ethyl acetate. Theorganic phase was dried over magnesium sulfate, filtered, concentratedand purified by silica gel chromatography affording the carboxylic acidas an off-white solid (295 mg, 56%). ES⁻ MS showed 504 m/z, the correctmass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=1.44 (s, 9H),4.89 (s, 2H), 6.97 t, 2H), 7.10 (m, 2H), 7.19 (m, 2H), 7.39 (m, 2H),8.02 (d, 1H), 8.20 (d, 2H), 8.78 (br s, 1H), 10.58 (s, 1H).

Example 1064-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)benzamide

Step 1:

The carboxylic acid from example 105 (100 mg, 0.20 mmol) was dissolvedin dichloromethane (3 mL), then treated with5-chloro-2-thiophensulfonamide (27 mg, 0.22 mmol), DMAP (27 mg, 0.22mmol) and EDC (42 mg, 0.22 mmol), then stirred at room temperatureovernight. The following day the reaction was determined to be completeby analytical HPLC and the mixture diluted with water, separated, thenextracted with ethyl acetate and the combined organic layers dried overmagnesium sulfate.

Step 2:

After filtration the solvent was removed and the crude residue treatedwith HCl in dioxane (4M, 5 mL) and stirred one hour. The solvent wasremoved in vacuo and the residue purified by preparative HPLC affordingthe desired aniline as a white powder. ES⁻ MS showed 583 m/z, thecorrect mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=4.21(s, 2H), 6.19 (s, 1H), 6.49 (d, 1H), 7.16 (t, 2H), 7.28 (d, 1H), 7.66(m, 3H), 7.44 (s, 1H), 7.56 (d, 1H), 7.73 (d, 1H), 7.92 (d, 2H) 11.16(s, 1H).

Example 107 methyl 4-amino-3-methoxybenzoate

Step 1:

3-methoxy-4-nitrobenzoic acid (2.00 g, 10.2 mmol) was added to asolution of methanol (10 mL) which had been treated with thionylchloride (1.46 mL, 20.4 mmol) at 0° C. The mixture was stirred at roomtemperature overnight, then concentrated, diluted with aqueous sodiumbicarbonate and extracted with dichloromethane affording the desiredmethyl ester in quantitative yield.

Step 2:

The nitro group was then reduced by treatment with 10% Pd/C (Degussa,200 mg) in ethyl acetate (20 mL) which was stirred under an atmosphereof hydrogen overnight. The following day the reaction mixture wasfiltered through celite and concentrated to give the aniline as a whitesolid (1.54 g, 83% for 2 steps). ¹H NMR (400 MHz, DMSO-d₆) showed δ=3.73(s, 3H), 3.78 (s, 3H), 5.59 (s, 2H), 6.60 (d, 1H), 7.28 (s, 1H), 7.35(dd, 1H).

Example 1084-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)-3-methoxybenzamide

Step 1:

The aniline from example 107 (198 mg, 1.09 mmol) and TEA (0.303 mL, 2.18mmol) in dichloromethane was added slowly to a solution ofdisuccinylcarbonate (280 mg, 1.09 mmol) in dichloromethane ((10 mL). Theresulting solution was stirred 30 min, then treated with the anilineprepared from 4-fluorobenyl bromide using procedure described in example1 (300 mg, 0.82 mmol) and stirred overnight at rt. The reaction mixturewas concentrated, then diluted with 10 mL of DMF and stirred at 90° C.until all material had been cyclized to the desired product. At thistime the reaction was worked up as described in example 33 and convertedto the title compound as described in example 34. ES⁻ MS showed 613 m/z,the correct mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showedδ=3.83 (s, 3H), 4.40 (s, 2H), 6.17 (s, 1H), 6.56 (dd, 1H), 7.06 (t, 2H),7.13 (d, 1H), 7.32 (d, 1H), 7.36 (ddd, 2H), 7.52 (dd, 1H), 7.56 (s, 1H),7.68 (d, 1H), 7.76 (d, 1H).

Example 1094-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)-3-fluorobenzamide

Step 1:

4-bromo-3-fluorobenzoic acid was converted to the methyl ester using theprocedure described in example 107.

Step 2:

The resulting methyl 4-bromo-3-fluorobenzoate (2.00 g, 8.6 mmol) wasdissolved in THF (30 mL) and treated with t-butylcarbamate (1.20 g, 10.3mmol) and cesium carbonate (5.61 g, 17.2 mmol), then degassed withargon. The solution was then treated with4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g, 0.65 mmol) andTris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol) and refluxedunder argon overnight. The following day the reaction was cooled,diluted with water and extracted with ethyl acetate twice and thecombined organic phases dried over magnesium sulfate. After filtrationand concentration the crude product was purified by silica gelchromatography affording the desired product as a light yellow solidwhich was immediately deprotected with HCl/dioxane (4 M, 15 mL). Afterstirring 3 hrs the reaction was diluted with 5 mL of ether and the solidfiltered affording the desired product as a light yellow solid (1.15 g,70%). ¹H NMR (400 MHz, DMSO-d₆) showed δ=3.83 (s, 3H), 7.28 (t, 1H),3.76 (m, 2H).

Step 3:

The above methyl 4-amino-3-fluorobenzoate hydrochloride (266 mg, 1.2mmol) and triethylamine (0.80 mL, 5.6 mmol) in dichloromethane (10 mL)was added slowly to a stirring solution of phosgene (1.89 M in toluene,1.27 mL, 2.4 mmol) in dichloromethane (10 mL). After the addition wascomplete the reaction mixture was stirred at rt for 1 hr, thenconcentrated and treated with the aniline prepared from 4-fluorobenylbromide using procedure described in example 1 (300 mg, 0.80 mmol) in 20mL dichloromethane and stirred overnight. The next day the reaction wasconcentrated, diluted with 10 mL of DMF and triethylamine (0.80 mL, 5.6mmol) then stirred at 90° C. until all material had cyclized to thedesired quinazolindione. The reaction mixture was cooled, diluted withwater, then extracted twice with ethyl acetate. The combined organicphases were concentrated and purified by silica gel chromatographyaffording the desired quinazolinedione methyl ester contaminated withthe symmetrical urea derived from the isocyanate.

This material was then converted to the title compound using theprocedure described in example 34. ES⁻ MS showed 601 m/z, the correctmass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=4.33 (s, 2H),6.19 (s, 1H), 6.51 (d, 1H), 7.15 (m, 3H), 7.34 (s, 2H), 7.50 (m, 2H),7.61 (m, 2H), 7.81 (m, 2H), 11.29 (s, 1H).

Example 1104-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)-2-methylbenzamide

The title compound was prepared from 4-bromo-2-methylbenzoic acid usingthe procedure described for example 109. ES⁻ MS showed 597 m/z, thecorrect mass for the product.

Example 1114-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)-2-methoxybenzamide

The title compound was prepared from methyl 4-amino-2-methoxybenzoateusing the procedure described for example 108. ES⁻ MS showed 613 m/z,the correct mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showedδ=3.90 (s, 3H), 4.39 (s, 2H), 6.18 (s, 1H), 6.57 (d, 1H), 6.93 (d, 1H),7.11 (m, 4H), 7.37 (dd, 2H), 7.70 (s, 1H), 7.73 (m, 2H).

Example 1124-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazoln-3(4H)-yl)-2-chloro-N-(5-chlorothiophen-2-ylsulfonyl)benzamide

The title compound was prepared from 4-bromo-2-chlorobenzoic acid usingthe procedure described for example 109. ES⁻ MS showed 617 m/z, thecorrect mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=4.31(s, 2H), 6.18 (s, 1H), 6.50 (d, 1H), 7.14 (t, 2H), 7.31 (m, 2H), 7.42(m, 2H), 7.60 (m, 2H), 7.79 (m, 2H), 11.14 (s, 1H).

Example 1134-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)-2-fluorobenzamide

The title compound was prepared from 4-bromo-2-fluorobenzoic acid usingthe procedure described for example 109. ES⁻ MS showed 601 m/z, thecorrect mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=4.31(s, 2H), 6.19 (s, 1H), 6.49 (d, 1H), 7.19 (m, 3H), 7.30 (d, 1H), 7.36(m, 2H), 7.45 (s, 1H), 7.57 (d, 1H), 7.67 (t, 1H), 7.73 (d, 1H), 11.14(s, 1H).

Example 1143-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)benzamide

The title compound was prepared from methyl 3-aminobenzoate using theprocedure described for example 108. ES⁻ MS showed 583 m/z, the correctmass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=4.30 (s, 2H),6.19 (s, 1H), 6.49 (d, 1H), 7.14 (t, 2H), 7.24 (s, 1H), 7.38 (m, 2H),7.43 (m, 1H), 7.53 (m, 3H), 7.70 (s, 1H), 7.79 (s, 1H), 7.90 (d, 1H),11.18 (s, 1H).

Example 1152-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-N-(5-chlorothiophen-2-ylsulfonyl)acetamide

The title compound was prepared from ethyl 4-aminophenylacetate usingthe procedure described for example 108. ES⁻ MS showed 597 m/z, thecorrect mass for the product. ¹H NMR (400 MHz, DMSO-d₆) showed δ=3.65(s, 2H), 4.30 (d, 2H), 6.18 (s, 1H), 6.49 (d, 1H), 7.14 (m, 3H), 7.22(m, 3H), 7.37 (m, 2H), 7.41 (m, 1H), 7.57 (d, 1H), 7.64 (d, 1H), 11.09(s, 1H).

Example 1164-((7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)-N-(5-chlorothiophen-2-ylsulfonyl)benzamide

The title compound was prepared from 4-aminomethylbenzoic acid using theprocedure described for example 107 step 1, followed by the proceduresfor example 108. ¹H NMR (400 MHz, DMSO-d₆) showed δ=4.28 (s, 2H), 5.04(s, 2H), 6.17 (s, 1H), 6.48 (d, 1H), 7.17 (t, 2H), 7.25 (s, 1H), 7.31(m, 4H), 7.58 (d, 1H), 7.70 (d, 1H), 7.81 (d, 2H), 11.09 (s, 1H).

Example 1174-(7-amino-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)benzamide

The title compound was synthesized from methyl2-amino-4-(tert-butoxycarbonyl)benzoate using a procedure similar toexample 106. ¹H NMR (400 MHz, DMSO-d₆) showed δ=6.21 (s, 1H), 6.40 (d,1H), 7.25 (d, 1H), 7.38 (d, 2H), 7.54 (d, 1H), 7.71 (s, 1H), 7.93 (d,2H), 11.18 (s, 1H).

Example 1184-(7-(benzylamino)-2,4-dioxo-1,2-dihydroquinazoln-3(4H)-yl)-N-(5-chlorothiophen-2-ylsulfonyl)benzamide

The aniline from example 117 (20 mg, 0.042 mmol) and benzaldehyde (7 μL,0.063 mmol) were dissolved in 10% acetic acid/methanol (2 mL) andstirred for 30 min. Then, sodium cyanoborohydride (6 mg, 0.84 mmol) wasadded and the reaction stirred at rt overnight. The next day thereaction mixture was concentrated and purified by preparative HPLCaffording the desired product as a white solid after lyophilization. ¹HNMR (400 MHz, DMSO-d₆) showed δ=4.32 (s, 2H), 6.20 (s, 1H), 6.49 (d,1H), 7.26 (s, 2H), 7.33 (m, 5H), 7.45 (s, 1H), 7.57 (d, 1H), 7.70 (s,1H), 7.92 (d, 2H), 11.16 (s, 1H).

Similarly, following the procedure described in Example 118, butreplacing benzaldehyde with other suitable aldehydes and ketones, andutilizing the modifications known to those skilled in the art, Examples119-140 were synthesized: TABLE 3 Example Structure ES-MS 119

(M − H)⁻ = 579 120

(M − H)⁻ = 595 121

(M − H)⁻ = 595 122

(M − H)⁻ = 583 123

(M − H)⁻ = 583 124

(M − H)⁻ = 601 125

(M − H)⁻ = 601 126

(M − H)⁻ = 601 127

(M − H)⁻ = 566 128

(M − H)⁻ = 566 129

(M − H)⁻ = 566 130

(M − H)⁻ = 599 131

(M − H)⁻ = 605 132

(M − H)⁻ = 579 133

(M + H)⁺ = 491 134

(M + H)⁺ = 505 135

(M − H)⁻ = 517 136

(M − H)⁻ = 517 137

(M − H)⁻ = 585 138

(M − H)⁻ = 531 139

(M − H)⁻ = 545 140

(M − H)⁻ = 559

Example 141

Pharmacological Assays

The pharmacological activity of each of the compounds according to theinvention is determined by the following in vitro assays:

I. Inhibition of ADP-Mediated Platelet Aggregation In Vitro

The effect of testing the compound according to the invention onADP-induced human platelet aggregation is preferably assessed in 96-wellmicrotiter assay (see generally the procedures in Jantzen, H. M. et al.(1999) Thromb. Hemost. 81:111-117). Human venous blood is collected fromhealthy, drug-free volunteers into ACD (85 mM sodium citrate, 111 mMglucose, 71.4 mM citric acid) containing PGI₂ (1.25 ml ACD containing1.6 μM PGI₂/10 ml blood; PGI₂ was from Sigma, St. Louis, Mo.).Platelet-rich plasma (PRP) is prepared by centrifugation at 160×g for 20minutes at room temperature. Washed platelets are prepared bycentrifuging PRP for 10 minutes at 730×g and resuspending the plateletpellet in CGS (13 mM sodium citrate, 30 mM glucose, 120 mM NaCl; 2 mlCGS/10 ml original blood volume) containing 1U/ml apyrase (grade V,Sigma, St. Louis, Mo.). After incubation at 37° C. for 15 minutes, theplatelets are collected by centrifugation at 730×g for 10 minutes andresuspended at a concentration of 3×10⁸ platelets/ml in Hepes-Tyrode'sbuffer (10 mM Hepes, 138 mM NaCl, 5.5 mM glucose, 2.9 mM KCl, 12 mMNaHCO₃, pH 7.4) containing 0.1% bovine serum albumin, 1 mM CaCl₂ and 1mM MgCl₂. This platelet suspension is kept >45 minutes at 37° C. beforeuse in aggregation assays.

Inhibition of ADP-dependent aggregation is preferably determined in96-well flat-bottom microtiter plates using a microtiter plate shakerand plate reader similar to the procedure described by Frantantoni etal., Am. J. Clin. Pathol. 94, 613 (1990). All steps are performed atroom temperature. The total reaction volume of 0.2 ml/well includes inHepes-Tyrodes buffer/0.1% BSA: 4.5×10⁷ apyrase-washed platelets, 0.5mg/ml human fibrinogen (American Diagnostica, Inc., Greenwich, Conn.),serial dilutions of test compounds (buffer for control wells) in 0.6%DMSO. After about 5 minutes preincubation at room temperature, ADP isadded to a final concentration of 2 μM which induces submaximalaggregation. Buffer is added instead of ADP to one set of control wells(ADP⁻ control). The OD of the samples is then determined at 490 nm usinga microtiter plate reader (Softmax, Molecular Devices, Menlo Park,Calif.) resulting in the 0 minute reading. The plates are then agitatedfor 5 min on a microtiter plate shaker and the 5 minute reading isobtained in the plate reader. Aggregation is calculated from thedecrease of OD at 490 nm at t=5 minutes compared to t=0 minutes and isexpressed as % of the decrease in the ADP control samples aftercorrecting for changes in the unaggregated control samples.

II. Inhibition of [³H]2-MeS-ADP Binding to Platelets

Having first determined that the compounds according to the inventioninhibit ADP-dependent platelet aggregation with the above assay, asecond assay is used to determine whether such inhibition is mediated byinteraction with platelet ADP receptors. Utilizing the second assay thepotency of inhibition of such compounds with respect to [³H]2-MeS-ADPbinding to whole platelets is determined. [³H]2-MeS-ADP bindingexperiments are routinely performed with outdated human plateletscollected by standard procedures at hospital blood banks. Apyrase-washedoutdated platelets are prepared as follows (all steps at roomtemperature, if not indicated otherwise):

Outdated platelet suspensions are diluted with 1 volume of CGS andplatelets pelleted by centrifugation at 1900×g for 45 minutes. Plateletpellets are resuspended at 3-6×10⁹ platelets/ml in CGS containing 1 U/mlapyrase (grade V, Sigma, St. Louis, Mo.) and incubated for 15 minutes at37° C. After centrifugation at 730×g for 20 minutes, pellets areresuspended in Hepes-Tyrode's buffer containing 0.1% BSA (Sigma, St.Louis, Mo.) at a concentration of 6.66×10 ⁸ platelets/ml. Bindingexperiments are performed after >45 minutes resting of the platelets.

Alternatively, binding experiments are performed with fresh humanplatelets prepared as described in I. (Inhibition of ADP-MediatedPlatelet Aggregation in vitro), except that platelets are resuspended inHepes-Tyrode's buffer containing 0.1% BSA (Sigma, St. Louis, Mo.) at aconcentration of 6.66×10⁸ platelets/ml. Very similar results areobtained with fresh and outdated platelets.

A platelet ADP receptor binding assay using the tritiated potent agonistligand [³H]2-MeS-ADP (Jantzen, H. M. et al. (1999) Thromb. Hemost.81:111-117) has been adapted to the 96-well microtiter format. In anassay volume of 0.2 ml Hepes-Tyrode's buffer with 0.1% BSA and 0.6%DMSO, 1×10⁸ apyrase-washed platelets are preincubated in 96-well flatbottom microtiter plates for 5 minutes with serial dilutions of testcompounds before addition of 1 nM [³H]2-MeS-ADP([³H]2-methylthioadenosine-5′-diphosphate, ammonium salt; specificactivity 48-49 Ci/mmole, obtained by custom synthesis from Amersham LifeScience, Inc., Arlington Heights, Ill., or NEN Life Science Products,Boston, Mass.). Total binding is determined in the absence of testcompounds. Samples for nonspecific binding may contain 10⁻⁵ M unlabelled2-MeS-ADP (RBI, Natick, Mass.). After incubation for 15 minutes at roomtemperature, unbound radioligand is separated by rapid filtration andtwo washes with cold (4-8° C.) Binding Wash Buffer (10 mM Hepes pH 7.4,138 mM NaCl) using a 96-well cell harvester (Minidisc 96, SkatronInstruments, Sterling, Va.) and 8×12 GF/C glassfiber filtermats (PrintedFiltermat A, for 1450 Microbeta, Wallac Inc., Gaithersburg, Md.). Theplatelet-bound radioactivity on the filtermats is determined in ascintillation counter (Microbeta 1450, Wallac Inc., Gaithersburg, Md.).Specific binding is determined by subtraction of non-specific bindingfrom total binding, and specific binding in the presence of testcompounds is expressed as % of specific binding in the absence of testcompounds dilutions.

The table below provides activity for selected compounds of theinvention, evaluated as described above. In the table below, activity inthe PRP assay is provided as follows: +++, IC₅₀<10 μM; ++, 10 μM<IC₅₀<30μM; and +, IC₅₀>30 μM. Example No. Activity Example 3 +++ Example 5 +++Example 12 +++ Example 16 +++ Example 21 +++ Example 41 ++ Example 51+++ Example 53 ++ Example 57 +++ Example 61 ++ Example 65 + Example 72++ Example 77 + Example 94 + Example 100 +++ Example 102 + Example 106+++ Example 113 +++

It should be understood that the foregoing discussion, embodiments andexamples merely present a detailed description of certain preferredembodiments. It will be apparent to those of ordinary skill in the artthat various modifications and equivalents can be made without departingfrom the spirit and scope of the invention. All the patents, journalarticles and other documents discussed or cited above are hereinincorporated by reference.

1. A compound having the formula:

wherein R is a member selected from the group consisting of H and C₁₋₆alkyl; R¹ is a member selected from the group consisting of H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl and C₃₋₅ cycloalkyl-alkyl; R² isa member selected from the group consisting of H, halogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, cyano and—C(O)R^(2a), wherein R^(2a) is a member selected from the groupconsisting of C₁₋₆ alkoxy and (C₁₋₆ alkyl)₀₋₂ amino; L is a 1 to 3carbon linking group selected from the group consisting of —CH₂—,—CH(CH₃)—, —CH₂CH₂—, —CH₂CH(CH₃)— and —CH₂CH₂CH₂—; L¹ is a linking groupselected from the group consisting of a bond and —CH₂—; L² is a linkinggroup selected from the group consisting of a bond, —NH— and —CH₂—; Ar¹is an aromatic ring selected from the group consisting of benzene,pyridine and pyrimidine, each of which is optionally substituted withfrom 1-2 R³ substituents, wherein each R³ is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy, (C₁₋₆alkyl)₀₋₂ amino, —C(O)R^(3a), —O(CH₂)_(m)OR^(3b), —(CH₂)_(m)OR^(3b),—O(CH₂)_(m)N(R^(3b))₂ and —(CH₂)_(m)N(R^(3b))₂, wherein the subscript mis an integer of from 1 to 3, each R^(3a) is a member independentlyselected from the group consisting of H, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, and each R^(3b) is a member independentlyselected from the group consisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl,and optionally, two R^(3b) groups attached to nitrogen are combined withthe nitrogen atom to form an azetidine, pyrrolidine or piperidine ring;Ar² is a 5-6 membered monocyclic or 9-10 membered fused-bicyclicaromatic ring system, optionally having from 1 to 3 heteroatoms selectedfrom N, O and S as ring vertices, said ring system being optionallysubstituted with from 1 to 3 R⁴ substituents wherein each of said R⁴substituents is independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino and—C(O)R^(4a), wherein each R^(4a) is a member independently selected fromthe group consisting of H, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and (C₁₋₆alkyl)₀₋₂ amino; the subscript t is 0 or 1 when L² is a bond, and is 1when L² is selected from —NH— and —CH₂—; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of claim 1, wherein R¹ is H orC₁₋₄ alkyl; L is selected from the group consisting of —CH₂—, —CH(CH₃)—and —CH₂CH₂—; L¹ is a bond and R² is selected from the group consistingof halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and—CONH₂.
 3. A compound of claim 1, wherein Ar¹ is a benzene ring,optionally substituted with 1-2 R³ substituents.
 4. A compound of claim1, wherein Ar¹ is a pyridine ring, optionally substituted with 1-2 R³substituents.
 5. A compound of claim 1, wherein Ar¹ is a pyrimidinering, optionally substituted with 1-2 R³ substituents.
 6. A compound ofclaim 3, wherein Ar² is benzene or naphthalene, each of which isoptionally substituted with from 1 to 3 R⁴ substituents.
 7. A compoundof claim 3, wherein Ar² is selected from the group consisting of furan,thiophene, thiazole, oxazole, thiadiazole, imidazole, pyrazole,pyridine, pyrimidine, benzothiophene, indole, quinoline, isoquinoline,benzofuran, benzimidazole, benzoxazole and benzothiazole, each of whichis optionally substituted with from 1 to 3 R⁴ substituents.
 8. Acompound of claim 7, wherein R¹ is H or C₁₋₄ alkyl; L is selected fromthe group consisting of —CH₂—, —CH(CH₃)— and —CH₂CH₂—; L¹ is a bond andR² is selected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂.
 9. A compound of claim 6,wherein R¹ is H or C₁₋₄ alkyl; L is selected from the group consistingof —CH₂—, —CH(CH₃)— and —CH₂CH₂—; L¹ is a bond and R² is selected fromthe group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, —CN, —C≡CH and —CONH₂.
 10. A compound of claim 1, having theformula:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to
 2. 11. A compound of claim 10, wherein R¹ is H; R² isselected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂; each R³, when present isindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from the group consisting of H, C₁₋₄ alkyl andC₁₋₄ alkanoyl; and each R⁴, when present is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.12. A compound of claim 11, wherein R² is halogen and is attached to the5-position of the thienyl ring; and each R⁴ when present isindependently selected from the group consisting of halogen, cyano andC₁₋₆ alkyl.
 13. A compound of claim 1, selected from the compoundsprovided in FIGS. 1-4.
 14. A compound of claim 3, wherein Ar² isselected from the group consisting of furan, thiophene, thiazole,oxazole, thiadiazole, imidazole, pyrazole, pyridine and pyrimidine, eachof which is optionally substituted with from 1 to 2 R⁴ substituents. 15.A compound of claim 14, wherein R¹ is H or C₁₋₄ alkyl; L is selectedfrom the group consisting of —CH₂—, —CH(CH₃)— and —CH₂CH₂—; and R² isselected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂.
 16. A compound of claim 3,wherein Ar² is selected from the group consisting of benzothiophene,indole, quinoline, isoquinoline, benzofuran, benzimidazole, benzoxazoleand benzothiazole, each of which is optionally substituted with from 1to 2 R⁴ substituents.
 17. A compound of claim 16, wherein R¹ is H orC₁₋₄ alkyl; L is selected from the group consisting of —CH₂—, —CH(CH₃)—and —CH₂CH₂—; and R₂ is selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂.
 18. Acompound of claim 1, having the formula:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to
 2. 19. A compound of claim 18, wherein Ar² is selected fromthe group consisting of furan, thiophene, thiazole, oxazole,thiadiazole, imidazole, pyrazole, pyridine and pyrimidine, each of whichis optionally substituted with from 1 to 2 R⁴ substituents.
 20. Acompound of claim 19, wherein R¹ is H; R² is selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN,—C≡CH and —CONH₂; each R³, when present is independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy,—O(CH₂)_(m)OR^(3b) and —O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is1 or 2 and each R^(3b) is independently selected from the groupconsisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and each R⁴, when presentis independently selected from the group consisting of halogen, cyano,hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.
 21. A compound of claim 20,wherein R² is halogen and is attached to the 5-position of the thienylring; and each R⁴ when present is independently selected from the groupconsisting of halogen, cyano and C₁₋₆ alkyl.
 22. A compound of claim 18,wherein Ar² is selected from the group consisting of benzothiophene,indole, quinoline, isoquinoline, benzofuran, benzimidazole, benzoxazoleand benzothiazole, each of which is optionally substituted with from 1to 2 R⁴ substituents.
 23. A compound of claim 22, wherein R¹ is H; R² isselected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂; each R³, when present isindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from the group consisting of H, C₁₋₄ alkyl andC₁₋₄ alkanoyl; and each R⁴, when present is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.24. A compound of claim 23, wherein R² is halogen and is attached to the5-position of the thienyl ring; and R⁴ when present is selected from thegroup consisting of halogen, cyano and C₁₋₆ alkyl.
 25. A compound ofclaim 1, having the formula:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to
 2. 26. A compound of claim 25, wherein Ar² is selected fromthe group consisting of furan, thiophene, thiazole, oxazole,thiadiazole, imidazole, pyrazole, pyridine and pyrimidine, each of whichis optionally substituted with from 1 to 2 R⁴ substituents.
 27. Acompound of claim 26, wherein R¹ is H; R² is selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN,—C≡CH and —CONH₂; each R³, when present is independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy,—O(CH₂)_(m)OR^(3b) and —O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is1 or 2 and each R^(3b) is independently selected from the groupconsisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and each R⁴, when presentis independently selected from the group consisting of halogen, cyano,hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.
 28. A compound of claim 27,wherein R² is halogen and is attached to the 5-position of the thienylring; and each R⁴ when present is independently selected from the groupconsisting of halogen, cyano and C₁₋₆ alkyl.
 29. A compound of claim 25,wherein Ar² is selected from the group consisting of benzothiophene,indole, quinoline, isoquinoline, benzofuran, benzimidazole, benzoxazoleand benzothiazole, each of which is optionally substituted with from 1to 2 R⁴ substituents.
 30. A compound of claim 29, wherein R¹ is H; R² isselected from the group consisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂; each R³, when present isindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from the group consisting of H, C₁₋₄ alkyl andC₁₋₄ alkanoyl; and each R⁴, when present is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.31. A compound of claim 30, wherein R² is halogen and is attached to the5-position of the thienyl ring; and each R⁴ when present isindependently selected from the group consisting of halogen, cyano andC₁₋₆ alkyl.
 32. A compound of claim 1, having the formula:

wherein the subscript n1 represents an integer of from 0 to 2, and R¹ isa member selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl and C₃₋₅ cycloalkyl-alkyl.
 33. A compound ofclaim 32, wherein R² is selected from the group consisting of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂; and eachR³, when present is independently selected from the group consisting ofC₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from the group consisting of H, C₁₋₄ alkyl andC₁₋₄ alkanoyl.
 34. A compound of claim 33, wherein R² is halogen and isattached to the 5-position of the thienyl ring.
 35. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of any of claims 1 to
 34. 36. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound havingthe formula:

wherein R is a member selected from the group consisting of H and C₁₋₆alkyl; R¹ is a member selected from the group consisting of H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl and C₃₋₅ cycloalkyl-alkyl; R² isa member selected from the group consisting of H, halogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, cyano and—C(O)R^(2a), wherein R^(2a) is a member selected from the groupconsisting of C₁₋₆ alkoxy and (C₁₋₆ alkyl)₀₋₂ amino; L is a 1 to 3carbon linking group selected from the group consisting of —CH₂—,—CH(CH₃)—, —CH₂CH₂—, —CH₂CH(CH₃)— and —CH₂CH₂CH₂—; L¹ is a linking groupselected from the group consisting of a bond and —CH₂—; L² is a linkinggroup selected from the group consisting of a bond, —NH— and —CH₂—; Ar¹is an aromatic ring selected from the group consisting of benzene,pyridine and pyrimidine, each of which is optionally substituted withfrom 1-2 R³ substituents, wherein each R³ is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy, (C₁₋₆alkyl)₀₋₂ amino, —C(O)R^(3a), —O(CH₂)_(m)OR^(3b), —(CH₂)_(m)OR^(3b),—O(CH₂)_(m)N(R^(3b))₂ and —(CH₂)_(m)N(R^(3b))₂, wherein the subscript mis an integer of from 1 to 3, each R^(3a) is a member independentlyselected from the group consisting of H, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, and each R^(3b) is a member independentlyselected from the group consisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl,and optionally, two R^(3b) groups attached to nitrogen are combined withthe nitrogen atom to form an azetidine, pyrrolidine or piperidine ring;Ar² is a 5-6 membered monocyclic or 9-10 membered fused-bicyclicaromatic ring system, optionally having from 1 to 3 heteroatoms selectedfrom N, O and S as ring vertices, said ring system being optionallysubstituted with from 1 to 3 R⁴ substituents wherein each of said R⁴substituents is independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino and—C(O)R^(4a), wherein each R^(4a) is a member independently selected fromthe group consisting of H, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and (C₁₋₆alkyl)₀₋₂ amino; the subscript t is 0 or 1 when L² is a bond, and is 1when L² is selected from —NH— and —CH₂—; or a pharmaceuticallyacceptable salt thereof.
 37. A pharmaceutical composition of claim 36,said compound having the formula:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to
 2. 38. A pharmaceutical composition of claim 37, wherein R¹is H; R² is selected from the group consisting of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂; each R³, whenpresent is independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy, —O(CH₂)_(m)OR^(3b) and—O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is 1 or 2 and each R^(3b)is independently selected from the group consisting of H, C₁₋₄ alkyl andC₁₋₄ alkanoyl; and each R⁴, when present is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl,C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.39. A method of treating thrombosis in a subject comprisingadministering to a subject in need thereof, a therapeutically effectiveamount of a compound of any of claims 1 to
 34. 40. A method of treatingthrombosis in a subject comprising administering to a subject in needthereof, a therapeutically effective amount of a compound having theformula:

wherein R is a member selected from the group consisting of H and C₁₋₆alkyl; R¹ is a member selected from the group consisting of H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₅ cycloalkyl and C₃₋₅ cycloalkyl-alkyl; R² isa member selected from the group consisting of H, halogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, cyano and—C(O)R^(2a), wherein R^(2a) is a member selected from the groupconsisting of C₁₋₆ alkoxy and (C₁₋₆ alkyl)₀₋₂ amino; L is a 1 to 3carbon linking group selected from the group consisting of —CH₂—,—CH(CH₃)—, —CH₂CH₂—, —CH₂CH(CH₃)— and —CH₂CH₂CH₂—; L¹ is a linking groupselected from the group consisting of a bond and —CH₂—; L² is a linkinggroup selected from the group consisting of a bond, —NH— and —CH₂—; Ar¹is an aromatic ring selected from the group consisting of benzene,pyridine and pyrimidine, each of which is optionally substituted withfrom 1-2 R³ substituents, wherein each R³ is independently selected fromthe group consisting of halogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy, (C₁₋₆alkyl)₀₋₂ amino, —C(O)R^(3a), —O(CH₂)_(m)OR^(3b), —(CH₂)_(m)OR^(3b),—O(CH₂)_(m)N(R^(3b))₂ and —(CH₂)_(m)N(R^(3b))₂, wherein the subscript mis an integer of from 1 to 3, each R^(3a) is a member independentlyselected from the group consisting of H, hydroxy, C₁₋₆ alkyl, C₁₋₆alkoxy, (C₁₋₆ alkyl)₀₋₂ amino, and each R^(3b) is a member independentlyselected from the group consisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl,and optionally, two R^(3b) groups attached to nitrogen are combined withthe nitrogen atom to form an azetidine, pyrrolidine or piperidine ring;Ar² is a 5-6 membered monocyclic or 9-10 membered fused-bicyclicaromatic ring system, optionally having from 1 to 3 heteroatoms selectedfrom N, O and S as ring vertices, said ring system being optionallysubstituted with from 1 to 3 R⁴ substituents wherein each of said R⁴substituents is independently selected from the group consisting ofhalogen, cyano, hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₃₋₅ cycloalkyl, C₃₋₅cycloalkyl-alkyl, C₃₋₅ cycloalkyl-alkoxy, (C₁₋₆ alkyl)₀₋₂ amino and—C(O)R^(4a), wherein each R^(4a) is a member independently selected fromthe group consisting of H, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy and (C₁₋₆alkyl)₀₋₂ amino; the subscript t is 0 or 1 when L² is a bond, and is 1when L² is selected from —NH— and —CH₂—; or a pharmaceuticallyacceptable salt thereof.
 41. A method in accordance with claim 40,wherein said compound is administered in combination with a secondtherapeutic agent selected from the group consisting of antiplateletcompounds, anticoagulants, fibrinolytics, anti-inflammatory compounds,cholesterol-lowering agents, blood pressure-lowering agents andserotonin blockers.
 42. A method in accordance with claim 41, whereinsaid second therapeutic agent is an antiplatelet compound selected fromthe group consisting of GPIIB-IIIa antagonists, aspirin,phosphodiesterase III inhibitors and thromboxane A2 receptorantoagonists.
 43. A method in accordance with claim 41, wherein saidsecond therapeutic agent is an anticoagulant selected from the groupconsisting of thrombin inhibitors, coumadin, heparin and Lovenox®.
 44. Amethod in accordance with claim 41, wherein said second therapeuticagent is an anti-inflammatory compound selected from the groupconsisting of non-steroidal anti-inflammatory agents, cyclooxygenase-2inhibitors and rheumatoid arthritis agents.
 45. A method in accordancewith claim 41, wherein said compound is administered orally.
 46. Amethod in accordance with claim 40, wherein said compound has theformula:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to 2; R¹ is H; R² is selected from the group consisting ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂;each R³, when present is independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy,—O(CH₂)_(m)OR^(3b) and —O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is1 or 2 and each R^(3b) is independently selected from the groupconsisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and each R⁴, when presentis independently selected from the group consisting of halogen, cyano,hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.
 47. A method for preventingthe occurrence of a secondary ischemic event comprising administering toa patient who has suffered a primary ischemic event a therapeuticallyeffective amount of a compound of claim 1, together with apharmaceutically acceptable carrier.
 48. A method in accordance withclaim 47, wherein said primary and/or secondary ischemic event isselected from the group consisting of myocardial infarction, stable orunstable angina, acute reocclusion after percutaneous transluminalcoronary angioplasty, restenosis, thrombotic stroke, transient ischemicattack, reversible ischemic neurological deficit and intermittentclaudication.
 49. A method in accordance with claim 47, wherein saidcompound has the formula:

wherein the subscripts n1 and n2 each independently represent an integerof from 0 to 2; R¹ is H; R² is selected from the group consisting ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, —CN, —C≡CH and —CONH₂;each R³, when present is independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₅ cycloalkyl-alkoxy,—O(CH₂)_(m)OR^(3b) and —O(CH₂)_(m)N(R^(3b))₂ wherein the subscript m is1 or 2 and each R^(3b) is independently selected from the groupconsisting of H, C₁₋₄ alkyl and C₁₋₄ alkanoyl; and each R⁴, when presentis independently selected from the group consisting of halogen, cyano,hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₃₋₅ cycloalkyl, C₃₋₅ cycloalkyl-alkyl, C₃₋₅cycloalkyl-alkoxy and (C₁₋₆ alkyl)₀₋₂ amino.